Between 2000 and 2009, demographics, clinical characteristics, and infection details were compared among patients undergoing simultaneous BTKA (SBTKA), staged or UTKA. 2825 (16%) patients underwent SB, 1151 (6%) staged, and 13,983 (78%) UTKA. The overall infection rate following SBTKA (0.57%) was lower compared to staged (1.39%) or UTKA (1.1%) (P = 0.01). The in-hospital infection rate was lower for the SB group (0.28% vs. 0.96% vs. 0.69%, respectively, P = 0.01). The rate of late infections was comparable between the groups (0.32% vs. 0.43% vs. 0.43%, respectively, P = 0.72). The rate of superficial infection was lower in the simultaneous cohort (0.28% vs. 1.04% vs. 0.87%; P = 0.003). The overall rate of deep infection and reoperation for infection was similar among the groups. Among patients with late infection, age, gender, comorbidity score, time to infection, and most common organism isolated were not significantly different between the groups. Among infected patients after SB or staged TKA, 3 SB patients (18.75%), and 3 staged (20%) had bilateral involvement (P = 1.0). Staged patients had more 2nd side infections, while simultaneous patients had more 1st side infections (P = 0.02). Regression analysis showed that UTKA patients were 2.5 times more likely to develop in-hospital infection compared to SBTKA, while staged patients were almost 3.4 times more likely. Each additional hospital day increased the risk of late infection by 11.3%. SBTKA demonstrates an advantage over staged and maintains the safety profile of unilateral approaches with respect to infectious complications.